2-isopropyl tetrahydro-1,3-substituted oxazines

ABSTRACT

COMPOUND OF THE FORMULA   2-(CH3-CH(-CH3)-),3-R2,6-(R1-CH2-)TETRAHYDRO-1,3-OXAZINE   IN WHICH: R1 IS METHOXY, PHENOXY OR MORPHOLINO, AND R2 IS HYDROGEN BENZOYL, SUBSTITUTED BENZOYL, P-TOLUENESULFONYL, ALKYLAMINOCARBONYL OR ARYLAMINOCARBONYL, IS PREPARED BY CYCLIZING   R1-CH2-CH(-OH)-CH2-CH2-NH2   TO PRODUCE THE COMPOUNDS OF THE FIRST-NAMED FORMULA IN WHICH R2 IS HYDROGEN. COMPOUNDS OF THE FIRST-NAMED FORMULA IN WHICH R2 IS OTHER THAN H ARE PREPARED BY ACYLATION. THE COMPOUNDS POSSESS ANALGESIC, ANTIINFLAMMATORY, ANALEPTIC RESPIRATORY, HYPOTENSIVE, SPASMOLYTIC AND ANTIULCEROUS PROPERTIES.

3,798,218 Patented Mar. 19, 1974 n fi d w Cl. 260-246 R 4 Claims ABSTRACT OF THE niscigosuuu Compounds of the formula '1 R is methoxy, phenoxy' or morpholino, and R, is hydrogen, benzoyl, substitutedfbenzoyl, p-tolhenesulfonyl, alkylaminocarbonyl or arylaminocarbonyl, is prepared by cyclizing j I The present inventiongrelates to niovel 2-isopropyl tetrahydro-1,3-substituted oxazines, their process of preparation and their therapeutic application. 2

The novel compounds-in accordance with the invention correspond to the general formula:;

in;which: Rfrepresen ts a methoxy, phcnoxy or morpholino radical,

and

R represents a hydrogen atom, an optionally-substituted benzoyl radical, a p-toluene-sulfonyl radical or an alkylor aryl-aminocarbonyl radical.

The process according to the invention comprises, in a first stage, cyclizing an amino-alcohol of formula:

in which R has the same signification as in Formula I, with the aid of isobutyraldehyde of formula:

v c-c H CH; 1)

to ;a compound of Formula I in which R: is a hydrogen atom, and then, if desired, acylating said compound of formula:

with a compound capable of furnishing a group, R having the same signification as in Formula I, except for. hydrogen.

When the radical Rg'of the Formula I is an optionallysubstituted benzoyl radical or a p-toluene-sulfonyl radical, the compound of Formula Ia is acylated with the aid of the corresponding acid chloride.

When the same radical R, is an alkylor aryl-amino carbonyl radical, the compound of Formula la is acylated withthe aid" of the corresponding isocyanate.

The following preparations are given by way of example toj illustrate the invention.

" "EXAMPLEl 90 g. of 1-phenoxy-4-amino-2-butanol are dissolved,

with warming to C., in 500 ml. of anhydrous benzene and then 40g. of isobutyraldehyde are added thereto, and

the mixture is heated to boiling. With the aid of a Dean- Stark apparatus, the water entrained by distillation of the benzene may-be recovered.

After ;2 hours of warming, the mixture is concentrated.

" The crude product obtained is purified by distillation under reduced pressure.

- Empirical formula=C H Nfi Elementary analysis.-Calculated (percent) C, 71.45;

H. 9.00; N. 5.95. Fauna (p a 7 .-2.6.2 839;.15...

EXAMPLE 2 2-isopropy1-3-benzoyl-6-phenoxymethyl tetrahydro-1,3-oxazine (Code No. 7047) Melting point=64 C. Yield=72% frmula=C H NO Elementary analysis.--Calculated (percentit C, 74.31; H, 7.42; N, 4.13. Found (percent): C, 74.46; H, 7.41; N, 4.19.

EXAMPLE 3 Z-isopropyl-6-phenoxymethyl-S-p-toluene sulfonyl tetrahydro-1,3-oxazine (Code No. 70169} 1 350 ml. of pyridine and 45 g. of 2-isopropyl-6-phenoxymethyl tetrahydro-LS-oXazine prepared by Example 1 are introduced into a 1 litre reaction vessel. The mixture is cooled to 0 C. and g. of p-toluenesulfonyl chloride in pyridine is slowly added thereto. After 2 hours in contact, the temperature of the mixture is allowed torriseto am: bient temperature and the mixture is diluted'with' 1.5,]. of water. The product which is precipitatedis dried and crystallized from isopropyl alcohol.

Melting point=88 0. r Yield=58% a 7 Empirical formula=C H NO S Elementary analysis.Calculated (percent): C, 64.75; H, 6.99; N,'3.60. Found (percent) 'C, 64.86;"H, 7.00; N,

I EXAMPLE 4 I 2-isopropyl-3-isopropyl aminocarbonyl-6-phenoxymethyl tetrahydro-l,3-oxazine (Code No. 7062)} .1, 47 g. ,of 2-isopropyl-fi-phenoxymethyl tetrahydro-1,3'- oxazine prepared byExample 1, and 2 ml. of pyridine are introduced into 300 ml. of benzene. There is slowly added thereto a benzene solution of isopropyl isocyanate' (17 g.). The temperature of the mixture progressively increases to about 30 CIAfterh'fu'rther 3 hours, the temperature-has increased to C. The benzene is then evaporated and the crude product is recrystallized from isopropyl ether.

Melting point=86 C. 1 k

Empirical f0rmula=C H N O Elementary mnalysis.-Calculated (percent):-C, 67.47;

H, 8.81; N, 8.47. Found (percent): C, 67.28; H, 8.84;

The following Table I indicates the identification"-characteristics of other compounds of Formula I, and gives..

in each case, the particular mode ofoperation' to b applied,

TABLE 1 Found 1 Y Boilin Melting Mode of operation point, C7. point, Yleld, appliedas Example 1..-.

percent; Empirical formula Code N0.

1-...do......-.- l.......

I 40 u CrtHaoNzOa 39- CroHziNOtS Same as abov 55 dam-N505 CieHuNaOa 10261..................' -ooH.

The compounds of Formula I have been studied on animals in the laboratory and have been shown to possess analgesic, antiinflammatory, analeptic respiratory, hypotensive, spasmolytic and antiulcerous properties.

(1) ANALGESIC PROPERTIES number of stretchings, percent Code No. of compound tested (2) AN TIINFLAMMATORY PROPERTIES The compounds of Formula I, administered by oral means on the rat, are capable of reducing the under-planatary oedema produced by the local injection of a phlogogenic agent, such as carraghenine.

By way of examples, administered in a dose of 200 mg./kg./PO the compounds No. 7062, 70261 and 70281 respectively reduce the under-planatary oedema by 65%, 65% and 40%.

(4) HY-POTENSIVE PROPERTIES Administered by intravenous means on the anasthetized rat, the compounds of Formula I provoke a lowering of the arterial pressure.

The results obtained with a certain number of compounds of Formula I are given in the following Table III.

TABLE III Dose ad- Lowering of arterial pressure ministered, Code No. of compound mg./kg./ Intensity, Duration, tested Lv. percent mn.

(5) SPASOMOLYTIC PROPERTIES The compounds of Formula I, introduced in the conserving medium, are capable of opposing the contractural action of barium chloride on the isolated duodenum of the rat. This activity is evaluated by taking papaverine as standard.

By way of example, the spasmolytic activity of compound No. 70280 is equivalent to that of papaverine.

(6) ANTIU'LCEROUS PROPERTIES The compounds of Formula I reduce the number of gastric ulcers provoked in the rat by the intraperitoneal injection of reserpine in a dose of 5 mg./kg., the said compounds being administered by oral means simultaneously.

By way of example, in a dose of 50 mg./kg./PO., the compound No. 70280 reduce the number of ulcers by One can see from the results shown above and those shown in the following Table IV, the diiference between the pharmacologically active dose and the lethal dose is sufficiently great to permit the compounds of Formula I to be used in therapeutics.

TABLE IV Dose ad- Percentage Code No. of comministered, mortality pound tested mg./kg./p.o. (mouse) The compounds of Formula I are useful in the treatment of inflammatory and other pains, hypertensions, respiratory insufiiciencies, digestive and other smooth fibre spasms, and gastro duodenal ulcers.

They may be administered by oral means in the form of tablets, drages and gelules containing 50 to 400 mg. of active ingredient (3 to 5 times a day) and by rectal means in the form of suppositories containing 50 to 200 mg. of active ingredient (1 or 2 times a day).

Accordingly, the present invension also relates to a therapeutic composition comprising a compound of the Formula I together with a therapeutically acceptable carrier.

What we claim is:

1. A compound of the formula:

on. O RP-CH: cg

in which:

R is methoxy, phenoxy or morpholino, and

R is hydrogen, benzoyl, p-chlorobenzoyl, p-toluene sulfonyl, isopropylaminocarbonyl or phenylaminocarbonyl.

2. A compound as claimed in claim 1, in which R is p-chlorobenzoyl.

3. A compound as claimed in claim 1, in which R, is isopropylaminocarbonyl or phenylaminocarbonyl.

4. A compound as claimed in claim 1, in which R is morpholino and R is p-chlorobenzoyl.

References Cited UNITED STATES PATENTS 3,707,541 12/1972 Lajiness 260244 3,558,615 6/1971 Haynes et al. 260244 3,385,828 5/1968 Kocher et al 260244 HARRY I. MOATZ, Primary Examiner US. Cl. X.R.

260244 R, 247.5 R, 570.6, 584 R; 4242 8 

